THERAPY IN PRACTICE

Drug Treatment of Hypertension in Pregnancy

Catherine M. Brown • Vesna D. Garovic

Published online: 20 February 2014

� Springer International Publishing Switzerland 2014

Abstract Hypertensive disorders represent major causes

of pregnancy-related maternal mortality worldwide. Simi-

lar to the non-pregnant population, hypertension is the most

common medical disorder encountered during pregnancy

and is estimated to occur in about 6–8 % of pregnancies. A

recent report highlighted hypertensive disorders as one of

the major causes of pregnancy-related maternal deaths in

the USA, accounting for 579 (12.3 %) of the 4,693

maternal deaths that occurred between 1998 and 2005. In

low-income and middle-income countries, preeclampsia

and its convulsive form, eclampsia, are associated with

10–15 % of direct maternal deaths. The optimal timing and

choice of therapy for hypertensive pregnancy disorders

involves carefully weighing the risk-versus-benefit ratio for

each individual patient, with an overall goal of improving

maternal and fetal outcomes. In this review, we have

compared and contrasted the recommendations from dif-

ferent treatment guidelines and outlined some newer per-

spectives on management. We aim to provide a clinically

oriented guide to the drug treatment of hypertension in

pregnancy.

1 Introduction

Hypertension in pregnancy includes a range of conditions,

most notably preeclampsia, a form of hypertension unique

to pregnancy that occurs de novo or may be superimposed

on chronic hypertension. The other forms, chronic and

gestational hypertension, usually have more benign courses

[1]. Preeclampsia, a pregnancy-specific disorder charac-

terized by hypertension (C140/90 mmHg) and proteinuria

(C300 mg in a 24-h urine), affects 3–4 % of all pregnan-

cies worldwide. However, recent obstetric literature ques-

tions the importance of kidney injury (as demonstrated by

proteinuria) in the diagnosis of preeclampsia, suggesting

that a subclass of ‘‘non-proteinuric preeclampsia’’ should

be added [2] or that detection of proteinuria should not be

mandatory for a preeclampsia diagnosis [3]. Risk factors

include primiparity, previous preeclampsia, increased

maternal body mass index (BMI) before pregnancy, eth-

nicity (Black women are more at risk), multiple gestations,

and underlying medical conditions, such as renal disease

and diabetes mellitus [4]. Preeclampsia is a condition that

involves numerous and constant interactions among the

placental, immunologic, and cardiovascular systems [5]. It

is a syndrome associated with impaired early placentation

and dysfunctional trophoblast development, defective pla-

cental angiogenesis, and an exaggerated maternal systemic

inflammatory response [6–9]. Risks to the fetus include

premature delivery, growth retardation, and death. Treat-

ment of severe hypertension is necessary to prevent cere-

brovascular, cardiac, and renal complications in the

mother.

In the US, the National High Blood Pressure Education

Program (NHBPEP) Working Group Report on High

Blood Pressure in Pregnancy was first presented in 1990

and most recently updated in 2000 [1]. The definition and

treatment recommendations for hypertension in pregnancy,

unlike those for hypertension in the general population,

have not similarly evolved and vary among different

organizations that provide guidance in this area. Blood

pressure (BP) levels requiring therapy in pregnancy,

although somewhat different among various groups and

C. M. Brown � V. D. Garovic (&)

Division of Nephrology and Hypertension, Department of

Medicine, Mayo Clinic College of Medicine, 200 First Street

SW, Rochester, MN 55905, USA

e-mail: garovic.vesna@mayo.edu

Drugs (2014) 74:283–296

DOI 10.1007/s40265-014-0187-7

professional societies, have been set, in general, at higher

systolic and diastolic levels than for the general population

[10]. There are several reasons for this. First, there was

(and still is) a relative paucity of well designed clinical

trials establishing the benefit of treatment of mild chronic

hypertension during pregnancy, typically defined in the

relevant literature as a systolic BP (SBP) 140–160 mmHg

and/or diastolic BP (DBP) 90–100 mmHg. As a result, the

current treatment approach is based on the assumption that

hypertension of 4–5 months duration in a young woman

without other risk factors does not increase her risk for

cardiovascular disease, neither during the pregnancy nor

later in life. However, there is increasing evidence that

hypertension in pregnancy is an under-recognized risk

factor for future cardiovascular disease (CVD). Compared

with women who have had normotensive pregnancies,

those who are hypertensive during pregnancy are at greater

risk of cardiovascular and cerebrovascular events years

after their pregnancies [11–13].

There is the concern that decreased BP in the mother

may compromise uteroplacental unit perfusion and fetal

circulation. With respect to antihypertensive therapy, the

choice has been limited to those that have proven to be

relatively safe, have long been in clinical use, and have a

side-effect profile that most obstetricians have found to be

acceptable [10].

Throughout the article, where available, we have ranked

the level of evidence in support for the measurement and

treatment of hypertension in pregnancy. A full explanation

of the ranking systems used is available in the appendices.

2 Measuring Blood Pressure (BP) in Pregnancy

The guidelines for measuring BP in pregnancy are outlined

in Table 1. Throughout this paper we refer to BP levels that

are based on clinic blood pressure measurements. There

has been much discussion on using ambulatory BP moni-

toring (ABPM) in pregnancy, but international guidelines

currently base diagnosis and treatment interventions on

clinic measurements.

3 Classification of Hypertension in Pregnancy

and Treatment Guidelines

According to NHBPEP and The American College of

Obstetricians and Gynecologists (ACOG) practice bulle-

tins, hypertension in pregnancy is classified as chronic

hypertension, preeclampsia-eclampsia, preeclampsia

superimposed upon chronic hypertension, and gestational

hypertension [1, 14, 15]. Chronic hypertension is defined as

BP C140/90 mmHg before pregnancy or \20th week of

gestation or use of antihypertensive medication before

pregnancy. Preeclampsia-eclampsia is a pregnancy-specific

disorder that occurs after 20 weeks gestation. Eclampsia is

the convulsive form of preeclampsia and affects 0.1 % of

all pregnancies. Preeclampsia can also occur superimposed

upon chronic hypertension. Gestational hypertension is

defined as new-onset BP C140 mmHg systolic or

90 mmHg diastolic on at least two occasions, at least 6 h

apart, after 20 weeks gestation, in the absence of protein-

uria. This category encompasses women with preeclampsia

who have not yet developed proteinuria, those with tran-

sient hypertension, if BP returns to normal by 12 weeks

postpartum, and women with chronic hypertension, if BP

elevation persists after 12 weeks.

The NHBPEP guidelines state that, in pregnancy, a

normal or acceptable BP is a SBP B140 and DBP

B90 mmHg, mild hypertension a SBP 140–150 or DBP

90–109 mmHg and severe hypertension a BP C160 sys-

tolic or C110 diastolic mmHg [1].

NHBPEP advises that antihypertensive medication

might be safely withheld in women with a history of

chronic hypertension, and recommend restarting treatment

at [150–160 mmHg SBP and/or 100–110 mmHg DBP, or

in the presence of left ventricular hypertrophy (LVH) or

renal insufficiency [1]. In preeclampsia, antihypertensive

therapy can be withheld unless there is a persistent DBP

105–110 mmHg or higher (III-C). ACOG Practice Bulle-

tins recommend that antihypertensive therapy be used for

women with a history of chronic hypertension who develop

severe hypertension in pregnancy, for maternal benefit, and

that treatment of uncomplicated mild hypertension is not

beneficial [14, 15].

The ACOG recently convened a task force on hyper-

tension in pregnancy and have provided an up-to-date

statement with recommendations on treatment of hyper-

tension in pregnancy [16]. They recommend that for

women with mild gestational hypertension or preeclampsia

(SBP \160 mmHg or DBP \110 mmHg), antihyperten-

sives are not recommended (the quality of this evidence is

moderate and the strength of this recommendation is

qualified). For women with preeclampsia and a sustained

SBP C160 mmHg or DBP C110 mmHg, antihypertensive

therapy is recommended (the quality of this evidence is

moderate and the strength of this recommendation is

strong). In pregnant women with chronic hypertension and

no end-organ damage, no antihypertensive therapy is nee-

ded if the SBP \160 mmHg or DBP \105 mmHg (the

quality of this evidence is low and the strength of this

recommendation is qualified). In pregnant women with

chronic hypertension who are on antihypertensive therapy,

the BP should be maintained between 120/80 mmHg and

160/105 mmHg (the quality of this evidence is low and the

strength of this recommendation is qualified).

284 C. M. Brown, V. D. Garovic

Table 1 Guidelines for the measurement of blood pressure in pregnancy

Guideline Measuring BP in pregnancy

SOGC [31] Rest for 5 min. Measure BP in the sitting position with the arm at the level of the heart (II-2A)

Use an appropriately sized cuff (i.e., length of 1.5 times the circumference of the arm) (II-2A)

Korotkoff phase V should be used to designate DBP (I-A)

If BP is consistently higher in one arm, the arm with the higher values should be used for all BP measurements (III-B)

BP can be measured using a mercury sphygmomanometer, calibrated aneroid device, or an automated BP device (validated for use in

preeclampsia) (II-2A)

Automated BP machines may underestimate BP in women with preeclampsia, and comparison of readings using mercury

sphygmomanometry or an aneroid device is recommended (II-2A)

ABPM (by 24-h or home measurement) may be useful to detect isolated office (white coat) hypertension (II-2B)

Patients should be instructed on proper BP measurement technique if they are to perform home BP monitoring (III-B)

NHBPEP [1] In gestational hypertension, DBP is determined as the disappearance of sound (Korotkoff 5)

Gestational BP elevation should be defined on the basis of at least two determinations. The repeat BP should be performed in a

manner that will reduce the likelihood of artifact and/or patient anxiety (Pr)

In preeclampsia, once BP starts to rise (this may be the first sign of developing preeclampsia), a repeat examination within 1–3 days is

recommended

In selected patients, BP may be checked at home

ACOG [14] Rest for 10 min or longer

Abstain from tobacco or caffeine use for 30 min before measurement (III)

Take BP in upright position

For patients in hospital, BP can be taken sitting up or in the left lateral recumbent position, patient’s arm at level of heart (III)

DBP is that pressure at which the sound disappears (Korotkoff phase 5) (III)

Use correct cuff size (length 1.5 times upper arm circumference, or a cuff with a bladder that encircles 80 % or more of arm)

Validated electronic devices can be used, but mercury sphygmomanometer is the preferred as being most accurate (III)

NICE [64] Remove tight clothing, ensure arm is relaxed and supported at heart level

Use cuff of appropriate size

Inflate cuff to 20–30 mmHg above palpated SBP, lower column slowly, by 2 mmHg per second or per beat

Read BP to the nearest 2 mmHg

Measure DBP at the disappearance of sounds (phase V)

SOMANZ [30] Sit comfortably, with legs resting on a flat surface

Use correct cuff size; if arm circumference [33 cm, use large cuff with inflatable bladder covering 80 % of arm

Measure BP in both arms at first visita

SBP is accepted as the first sound heard (K1) and the DBP at the disappearance of sounds completely (K5). Where K5 is absent, K4

(muffling) should be accepted

Mercury sphygmomanometers are the gold standard, but if using an automated device, validate against mercury sphygmomanometer

Regular calibration of devices needed (ideally monthly)

24-h ABPM – Useful for the evaluation of early hypertension (\20 weeks gestation), where one-third of women will have ‘white

coat’ hypertension and half of these women will go on to have ABPM confirmed hypertension later in pregnancy

ABPM less useful for screening for ‘white coat’ hypertension in second half of pregnancy

ESH on ABPM

[65]

ABPM particularly useful for detecting white-coat and nocturnal hypertension in pregnancy

White-coat hypertension has a more favorable outcome than sustained hypertension diagnosed by ABPM

Nocturnal hypertension is higher in women with preeclampsia than in those with gestational hypertension, and is associated with more

maternal and fetal complications

The predictive accuracy of ABPM remains low; ambulatory pulse pressure and daytime DBP have been shown to be predictive of

birth weight

The abbreviations/key codes in parentheses represent the ranking of evidence and grading of recommendations used by the SOGC, by NHBPEP Working

Group Report on High Blood Pressure and ACOG. An explanation of these can be found in the appendices

ABPM ambulatory blood pressure monitoring, ACOG American College of Obstetricians and Gynecologists, BP blood pressure, DBP diastolic blood

pressure, ESH on ABPM European Society of Hypertension position paper on Ambulatory Blood Pressure Monitoring, ESH/ESC European Society of

Hypertension/European Society of Cardiology, NHBPEP National High Blood Pressure Education Program Working Group Report on High Blood

Pressure, NICE National Institute for Health and Care Excellence, SBP systolic blood pressure, SOGC Society of Obstetricians and Gynaecologists of

Canada, SOMANZ Society of Obstetric Medicine of Australia and New Zealanda Variation in BP between upper limbs should be \10 mmHg

Drug Treatment of Hypertension in Pregnancy 285

Other international societies and organizations have

different definitions and levels at which therapy should

be initiated and these are also presented in Table 2.

These recommendations come from the Society of

Obstetricians and Gynaecologists of Canada (SOGC), the

European Society of Hypertension/European Society of

Cardiology (ESH/ESC), the UK National Institute for

Health and Care Excellence (NICE), and the Society of

Obstetric Medicine of Australia and New Zealand

(SOMANZ).

4 Drug treatment of Hypertension in Pregnancy

According to the NHBPEP, methyldopa, labetalol, beta-

blockers (other than atenolol), slow-release nifedipine, and

a diuretic in pre-existing hypertension are considered as

appropriate treatment [1]. If a woman’s BP is well con-

trolled on an agent pre-pregnancy, she may continue it

during pregnancy, with the exception of angiotensin-con-

verting enzyme (ACE) inhibitors and angiotensin II

receptor blockers (ARBs). If restarting drug therapy in

women with chronic hypertension, methyldopa is recom-

mended as first-line therapy. For emergency treatment in

preeclampsia, intravenous hydralazine, labetalol, and oral

nifedipine can be used [1]. The ACOG Practice Bulletins

also recommend that methyldopa and labetalol are appro-

priate first-line agents, and that beta-blockers and ACE

inhibitors are not recommended [14, 15].

In current practice, antihypertensive medications other

than methyldopa and hydralazine are being used more

often in pregnancy (Table 3), and particularly in patients

Table 2 Guidelines for diagnosis and treatment of hypertensive disorders of pregnancy (adapted from Moser et al. [68])

SOGC [31] ESH/ESC [42, 66] NICE [43] SOMANZ [30]

Definitions of HTN in pregnancy

A. Pre-existing HTN (before

pregnancy or \20 weeks)

(1) with co morbid conditions (2)

with preeclampsia (HTN, PU, and

adverse conditions, [20 weeks’

gestation)

B. GHTN (C20 weeks)

(1) with co morbid conditions (2)

with preeclampsia (HTN, PU, and

adverse conditions)

A. Pre-existing HTN

B. Preeclampsia-GHTN with

significant PU

C. GHTN

D. Pre-existing HTN plus

superimposed GHTN with PU

E. Antenatally unclassifiable HTN-

postpartum re-classified as (1)

GHTN with or without PU, (2) pre-

existing HTN

A. Primary or Secondary chronic

HTN

\20 weeks’ gestation or on

antihypertensive meds before

referral to maternity service

B. Preeclampsia-new HTN

[20 weeks with significant PU

(1) mild, (2) moderate, (3) severe

HTN

Eclampsia (convulsive form of

preeclampsia)

C. GHTN-new HTN [20 weeks

without significant PU

(1) mild, (2) moderate, (3) severe

HTN

A. Chronic HTN

(1) essential, (2)

secondary, or (3) white

coat

B. Preeclampsia-

eclampsia

C. GHTN

D. Preeclampsia

superimposed upon

chronic HTN

Recommended BP tx levels

Severe HTN ([160/C110 mmHg),

BP should be lowered to

\160 mmHg SBP and

\110 mmHg DBP (II-2B)

Nonsevere HTN (140–159/

90–109 mmHg), BP should be

lowered to 130–155 mmHg SBP

and 80–105 mmHg DBP, when

there are no comorbid conditions

(III-C)

For women with comorbidities,

SBP should be lowered to

130–139 mmHg, and DBP to

80–89 mmHg (III-C)

Drug tx of severe HTN in pregnancy

(SBP [160 mmHg or DBP

[110 mmHg) is recommended

(I-C)

Drug tx may also be considered in

pregnant women with persistent

elevation of BP C150/95 mmHg,

and in those with BP C140/

90 mmHg in the presence of

GHTN, subclinical organ damage

or symptoms (II-bC)

In pregnant women with

uncomplicated chronic HTN, aim

to keep blood pressure lower than

150/100 mmHg. Do not lower

diastolic blood pressure below

80 mmHg

Offer pregnant women with target-

organ damage secondary to chronic

HTN (for example, kidney disease)

tx, with the aim of keeping BP

lower than 140/90 mmHg

In preeclampsia and GHTN, treat

only if BP C150/100 mmHg

Antihypertensive tx be

commenced in all

women with SBP

C170 mmHg or DBP

C110 mmHg

Tx for mild to moderate

HTN of 140–160/

90–100 mmHg is

optional and will reflect

local practice

The abbreviations/key codes in parentheses represent the ranking of evidence and grading of recommendations used by the SOGC and the ESH/

ESC. An explanation of these can be found in the appendices

BP blood pressure, ESH/ESC European Society of Hypertension/European Society of Cardiology, GHTN gestational hypertension, HTN

hypertension, NICE National Institute for Health and Care Excellence, PU proteinuria, SOGC Society of Obstetricians and Gynaecologists of

Canada, SOMANZ Society of Obstetric Medicine of Australia and New Zealand, tx treatment

286 C. M. Brown, V. D. Garovic

Ta

ble

3R

eco

mm

end

edm

anag

emen

to

pti

on

sfo

rtr

eati

ng

hy

per

ten

sio

nin

pre

gn

ancy

Dru

gtr

eatm

ent

Do

sed

aily

[18

,2

6]

FD

A

clas

s

Saf

ety

Sid

eef

fect

sB

reas

tfe

edin

ga

Fir

st-l

ine

ag

ents

Met

hy

ldo

pa

(F),

(I-A

)

Dru

go

fch

oic

ea

cco

rdin

g

toa

llg

rou

ps

0.5

–3

g/d

ayin

2d

ivid

edd

ose

sB

Pro

ven

safe

tyan

def

fica

cyS

om

eco

nce

rnw

ith

dep

ress

ion

,h

epat

ic

dis

turb

ance

s,h

emo

lyti

can

emia

-m

ay

no

tlo

wer

BP

adeq

uat

ely

Co

mp

atib

lew

ith

BM

Lab

etal

ol

(M),

(I-A

)2

00

–1

,20

0m

g/d

ayP

Oin

2–

3

div

ided

do

ses

20

–4

0m

gIV

(max

22

0m

g

tota

l)

CS

afet

ysi

mil

arto

met

hy

ldo

pa,

may

be

mo

re

effi

caci

ou

sth

anm

eth

yld

op

a

May

be

asso

ciat

edw

ith

feta

lg

row

th

rest

rict

ion

Neo

nat

alh

yp

og

lyce

mia

wit

hla

rger

do

ses

Usu

ally

com

pat

ible

wit

hB

M

Sec

on

d-l

ine

ag

ents

Nif

edip

ine

lon

g-a

ctin

g(R

a),

(I-A

)

10

–3

0m

gP

OC

Wid

ely

use

dM

ayin

hib

itla

bo

r;ra

rely

,p

rofo

un

d

hy

po

ten

sio

nif

sho

rt-a

ctin

gag

ent

isu

sed

wit

hm

agn

esiu

m

Usu

ally

com

pat

ible

wit

hB

M

Ver

apam

il8

0m

gti

dP

OC

Sim

ilar

effi

cacy

too

ther

ora

lag

ents

Ris

ko

fin

tera

ctio

nw

ith

mag

nes

ium

—

bra

dy

card

ia

Usu

ally

com

pat

ible

wit

hB

M

Clo

nid

ine

Alt

ern

ati

veo

pti

on

0.1

–0

.6m

g/d

ayin

2d

ivid

ed

do

ses

CS

afet

ysi

mil

arto

met

hy

ldo

pa

Lim

ited

dat

are

gar

din

gfe

tal

safe

ty

Effi

cacy

sim

ilar

tom

eth

yld

op

aP

oss

ible

BM

effe

cts

Hy

dro

chlo

roth

iazi

de

Use

ful

inch

ron

icH

TN

12

.5–

25

mg

/day

BV

olu

me

con

trac

tio

n,

elec

tro

lyte

abn

orm

alit

ies—

rare

wit

hsm

all

do

ses

May

red

uce

BM

pro

du

ctio

n

Hy

dra

lazi

ne

(F,

Re)

No

tre

com

men

ded

by

ES

H

[42

,6

6]

50

–3

00

mg

/day

in2

–4

div

ided

do

ses

DE

ffica

cio

us

IVag

ent

Po

ssib

lem

ater

nal

po

lyn

euro

pat

hy

,d

rug

-

ind

uce

dlu

pu

s,n

eon

atal

lup

us

and

thro

mb

ocy

top

enia

;T

ach

yp

hy

lax

is

Usu

ally

com

pat

ible

wit

hB

M

Ate

no

lol

(Ate

no

lol

no

tre

com

men

ded

)(I

-D)

Ate

no

lol

has

risk

of

gro

wth

rest

rict

ion

wh

enst

arte

din

firs

to

rse

con

dtr

imes

ter

and

isn

ot

reco

mm

end

edif

bre

ast

feed

ing

Dia

zox

ide

30

–5

0m

gIV

ever

y5

–1

5m

in;

IVb

olu

sfo

rac

ute

BP

low

erin

gin

sev

ere

HT

N[3

0]

Pra

zosi

n0

.5–

5m

gti

d;

con

sid

ered

ase

con

d-l

ine

agen

tb

yS

OM

AN

Z[3

0]

No

tre

com

men

ded

by

SO

GC

[31]

(I-D

)

Ass

oci

ated

wit

hp

ost

ura

lh

yp

ote

nsi

on

and

pal

pit

atio

ns

Ox

pre

no

lol

(b-b

lock

erw

ith

ISA

)

20

–1

60

mg

tid

;a

firs

t-li

ne

agen

tb

yS

OM

AN

Z[3

0]

Co

ntr

ain

dic

ated

inh

eart

blo

ck

Nit

rop

russ

ide

On

lyco

nsi

der

edfo

rli

fe-t

hre

aten

ing

sev

ere

HT

N

Cy

anid

ean

dth

iocy

anat

eto

xic

ity

,m

ust

be

care

full

ym

on

ito

red

Als

ori

sko

fca

rdio

-neu

rog

enic

syn

cop

e

Co

ntr

ain

dic

ated

[26

]A

CE

Is,

AR

Bs

(Pr,

Re)

,(I

I-2

E),

FD

AC

lass

D

Dir

ect

ren

inin

hib

ito

rs

Sp

iro

no

lact

on

en

ot

reco

mm

end

edd

ue

top

ote

nti

alfe

tal

anti

and

rog

enef

fect

s

Drug Treatment of Hypertension in Pregnancy 287

for whom BP control cannot be achieved with these agents,

or in the presence of intolerable side effects.

The drug treatments for severe acute hypertension in

preeclampsia are highlighted in Fig. 1 [1]. Severe hyper-

tension in preeclampsia being defined as a BP

C160 mmHg systolic, C105 mmHg diastolic, or both.

5 Profiles of Recommended Drug Therapies

5.1 Centrally Acting a2-Adrenergic Agonists

Methyldopa is a centrally acting a2-adrenergic receptor

agonist. It inhibits vasoconstriction via a central mecha-

nism by reducing catecholamine release [17]. It decreases

central sympathetic outflow, decreasing systemic vascular

resistance without decreasing cardiac output [18]. The side

effects of methyldopa include fatigue, depression, poor

sleep, and decreased salivation. Dose-independent adverse

effects include elevated liver enzymes in up to 5 % of

women, and some patients can develop a positive antinu-

clear antigen or antiglobulin (Coombs’) test, although a

clinical hemolytic anemia is rare [18, 19]. It has been

suggested that methyldopa should be avoided in women

with a prior history of depression, because of the possible

increased risk of postnatal depression [20]. Methyldopa has

a long history of use in pregnancy and does not appear

teratogenic [18]. Methyldopa has a record of safety in

pregnancy, as established by follow-up studies in the 1980s

of children exposed to the drug in utero [21]. More recent

studies indicate that, in hypertensive pregnancy disorders,

treatment with methyldopa does not affect the maternal

uterine artery Doppler pulsatility and resistance indices,

suggesting that it does not impair uteroplacental circulation

and consequent fetal growth [22]. The doses of methyldopa

recommended in pregnancy are similar to those used in

non-pregnant patients [23].

Clonidine is a centrally acting adrenergic agonist. It

works as an antihypertensive agent by stimulating a-2

adrenergic receptors in the brainstem, thereby decreasing

central adrenergic output [24]. It acts on both peripheral

and central a2-adrenergic receptors to decrease the cardiac

output, systemic vascular resistance, SBP, and heart rate

[25]. Clonidine is similar to methyldopa with respect to

safety and efficacy [25]. It is used generally as a third-line

agent for multidrug control of refractory hypertension

[19].

According to the US FDA, methyldopa is a Class B

drug and clonidine is a Class C drug. According to either

the World Health Organization (WHO) and/or Thomson

lactation ratings, methyldopa is usually compatible with

breast milk and clonidine has possible breast-milk

effects.Ta

ble

3co

nti

nu

ed

Dru

gtr

eatm

ent

Do

sed

aily

[18

,2

6]

FD

A

clas

s

Saf

ety

Sid

eef

fect

sB

reas

tfe

edin

ga

Oth

erm

an

ag

emen

tst

rate

gie

s

Lo

w-d

ose

asp

irin

Use

adv

ised

inw

om

enat

hig

hri

sk

Use

dp

rop

hy

lact

ical

lyin

wo

men

wit

ha

his

tory

of

pre

ecla

mp

sia

at\

28

wee

ks

Fis

ho

ilsu

pp

lem

enta

tio

nN

ot

reco

mm

end

ed

Cal

ciu

msu

pp

lem

enta

tio

nM

ayh

ave

role

ind

ecre

asin

gin

cid

ence

of

pre

ecla

mp

sia

Ro

lein

low

calc

ium

inta

ke

po

pu

lati

on

s

Vit

amin

Can

dE

No

tre

com

men

ded

Ste

roid

ther

apy

On

lyfo

rfe

tal

lun

gm

atu

rati

on

aA

cco

rdin

gto

eith

erth

eW

orl

dH

ealt

hO

rgan

izat

ion

and

/or

Th

om

son

lact

atio

nra

tin

gs

Th

eab

bre

via

tio

ns

inp

aren

thes

esre

pre

sen

tth

ety

pes

of

stu

die

sth

atp

rov

ided

the

evid

ence

bas

efo

rth

ere

com

men

dat

ion

sfr

om

the

NH

BP

EP

and

the

key

cod

esfr

om

the

evid

ence

bas

eu

sed

by

the

SO

GC

.A

nex

pla

nat

ion

of

thes

eca

nb

efo

un

din

the

app

end

ices

AC

EI

ang

iote

nsi

n-c

on

ver

tin

gen

zym

ein

hib

ito

r,A

RB

ang

iote

nsi

on

IIre

cep

tor

blo

cker

,B

Mb

reas

tm

ilk

,B

Pb

loo

dp

ress

ure

,E

SH

Eu

rop

ean

So

ciet

yo

fH

yp

erte

nsi

on

,F

DA

US

Fo

od

and

Dru

g

Ad

min

istr

atio

n,

HT

Nh

yp

erte

nsi

on

,IS

Ain

trin

sic

sym

pat

ho

mim

etic

acti

vit

y,

IVin

trav

eno

us,

NH

BP

EP

Nat

ion

alH

igh

Blo

od

Pre

ssu

reE

du

cati

on

Pro

gra

m,

PO

per

ora

l,S

OG

CS

oci

ety

of

Ob

stet

rici

ans

and

Gy

nae

colo

gis

tso

fC

anad

a,S

OM

AN

ZS

oci

ety

of

Ob

stet

ric

Med

icin

eo

fA

ust

rali

aan

dN

ewZ

eala

nd

,ti

dth

ree

tim

esd

aily

288 C. M. Brown, V. D. Garovic

5.2 Peripherally Acting Adrenergic-Receptor

Antagonists

Labetalol, a non-selective b-blocking agent with vascular

a1-receptor-blocking capabilities is widely used in preg-

nancy [26]. Fetal growth restriction and low placental

weight in patients (with essential hypertension) have been

associated with the use of atenolol during the second tri-

mester [27], but not with other b-blocking agents, such as

labetalol (an a- and b-blocker), which is used frequently

for the treatment of severe acute hypertension during

pregnancy, and has shown equivalent efficacy and better

tolerability than hydralazine [28]. Side effects, including

fatigue, lethargy, exercise intolerance, sleep disturbance,

and bronchoconstriction, have been reported [26]. b-

blockers are not associated with teratogenicity [26].

In a review of antihypertensive drug therapy for mild-to-

moderate hypertension during pregnancy, b-blockers

appear to be more effective than methyldopa in limiting

episodes of severe hypertension in women with hyperten-

sive disorders of pregnancy [29]. However, at the same

time, this review showed no evidence of a difference in the

risks of preeclampsia, neonatal death, preterm birth, or

small-for-gestational-age (SGA) babies.

Prazosin is an a1-blocker that selectively blocks post-

synaptic a1-adrenoceptors, producing a decrease in total

peripheral resistance (and a reflex increase in sympathetic

tone) [18]. It is considered as a second-line agent by SO-

MANZ [30], but is not recommended by SOGC [31].

Prazosin has a useful role in chronic renal disease com-

plicating pregnancy. It is associated with postural hypo-

tension and palpitations.

Fetal growth restriction and low placental weight in

patients (with essential hypertension) have been associated

with the use of atenolol during the second trimester [27],

but not with other b-blocking agents, such as labetalol (an

a- and b-blocker), which is used frequently for the treat-

ment of severe acute hypertension during pregnancy, and

has shown equivalent efficacy and better tolerability than

hydralazine [28]. The benefits and concerns of antihyper-

tensive agents are outlined in Table 2.

According to the FDA, labetalol is a Class C drug. It may

be associated with a risk of fetal bradycardia and neonatal

hypoglycemia. According to either the WHO and/or

Thomson lactation ratings, methyldopa is usually compati-

ble with breast milk. Atenolol is an FDA Class D drug. It is

not recommended due to risk of intrauterine growth restric-

tion (IUGR) and is not recommended if breast feeding.

5.3 Calcium Channel Blockers

Oral nifedipine and verapamil are frequently seen as second-

line agents used for the treatment of hypertension in preg-

nancy. They do not appear to be teratogenic [32]. Calcium

channel blockers (CCBs) inhibit the influx of calcium ions to

vascular smooth muscle, resulting in arterial vasodilation;

nifedipine acts predominantly on the vasculature and

verapamil acts primarily on the heart [18, 17]. Side effects of

CCB use in the mother include tachycardia, palpitations,

peripheral edema, headaches, and facial flushing [33].

According to the FDA, nifedipine and verapamil are Class

C drugs. With all CCBs, there is a risk of interactions with

magnesium, resulting in profound hypotension. Nifedipine

and verapamil are usually compatible with breast feeding.

5.4 Direct Vasodilators

Hydralazine is now predominantly used intravenously for

the treatment of severe hypertension in pregnancy.

Hydralazine selectively relaxes arteriolar smooth muscle.

Fig. 1 Drug treatments and

regimens for severe

hypertension in preeclampsia

[1]. *The NHBPEP Working

Group recommends the use of

sodium nitroprusside in rare

cases of hypertension not

responding to the previously

mentioned drugs, or clinical

findings of hypertensive

encephalopathy, or both.

NHBPEP National High Blood

Pressure Education Program

Drug Treatment of Hypertension in Pregnancy 289

Adverse effects include headache, nausea, flushing, and

palpitations. It does not appear teratogenic. There have

been reports of neonatal thrombocytopenia, rare cases of a

pyridoxine-responsive polyneuropathy with chronic use,

and drug-induced lupus [34].

However, there is evidence that intravenous labetalol or

oral nifedipine are preferable first-line agents compared

with intravenous hydralazine in severe hypertension in

pregnancy [28].

Sodium nitroprusside is rarely used in pregnancy and is

reserved for life-threatening severe hypertension [35].

Adverse effects include cyanide and thiocyanate toxicity,

and also the risk of cardio-neurogenic syncope.

Hydralazine is an FDA Class C drug. It is usually

compatible with breast feeding.

5.5 Diuretics

The use of diuretic therapy during pregnancy remains con-

troversial, primarily due to theoretical concerns about

reduced plasma volume. In a randomized trial of women with

chronic hypertension in pregnancy, the use of diuretics

reduced plasma volume, but was not associated with adverse

pregnancy outcomes [36]. Women on maintenance diuretic

therapy prior to pregnancy can be continued on this regimen,

unless they develop premonitory signs of preeclampsia, such

as proteinuria. At that point, some physicians would opt to

stop diuretic medications, due to the concern that, with the

lower plasma volume characteristic of preeclampsia, the use

of diuretics may further aggravate the hypovolemic state,

stimulate the renin–angiotensin system, and worsen hyper-

tension [37]. However, the 2000 NHBPEP Working Group

Report recognized that the major concern for the use of

diuretics in pregnancy is primarily theoretical, as supporting

evidence for their deleterious effects is lacking.

Thiazides are FDA Class B drugs. They may cause

volume contraction and electrolyte abnormalities, but this

is rare with small doses. Diuretics may reduce milk pro-

duction [19]. Spironolactone is not recommended due to

potential fetal antiandrogen effects.

5.6 Renin–Angiotensin System Drugs

ACE inhibitors and ARBs are contraindicated in pregnancy

due to their association with adverse fetal effects [38].

ACE inhibitors are labeled FDA class C for the first tri-

mester of pregnancy, and FDA class D for the second and

third trimesters.

5.7 Current Clinical Practice

As discussed in earlier sections, there are several guidelines

and recommendations available to practitioners treating

hypertension in pregnancy. However, these may not always

reflect clinical practice. Two recent reviews give us an

indication of actual drug therapy being used in hyperten-

sion in pregnancy. Table 4 summarizes drug therapy cur-

rently being used in clinical practice to treat very high

blood pressure in pregnancy.

There is further evidence of the increasing use of anti-

hypertensives in pregnancy. A review of outpatient anti-

hypertensive medication use during pregnancy in a

Medicaid population was performed from 2000 to 2006

[39]. It noted that the prevalence of antihypertensive use,

both in the first trimester and in pregnancy overall,

increased during this period by approximately 50 %; by the

end, nearly 5 % of all pregnancies were exposed to anti-

hypertensive therapy [39]. The authors reported significant

variation in the range of antihypertensive drugs used across

all trimesters of pregnancy and in the approach to the

management of patients entering pregnancy on antihyper-

tensive medication. There were study limitations, but a

significant number of women taking antihypertensives

prior to pregnancy were kept on their same drug and not

switched to one of the preferred agents. b-blockers, thia-

zides, and CCBs were often used as first-line agents.

6 Drugs Used for the Prevention of Preeclampsia/

Eclampsia

6.1 Magnesium Sulphate and Other Anticonvulsants

for Preeclampsia

In a Cochrane review of treatment of women with pre-

eclampsia, magnesium sulphate more than halves the risk

of eclampsia, and probably reduces maternal death [40]. In

women with eclampsia, magnesium sulphate reduces the

risk ratio of maternal death and of recurrence of seizures,

compared with diazepam.

6.2 Antiplatelet Agents and Preeclampsia

A review of 59 trials, involving 37,560 women, found that

low doses of aspirin reduced the risk of preeclampsia by

17 %, the risk of fetal or neonatal deaths by 14 %, and the

relative risk of preterm births by 8 % [41]. Doses of up to

75 mg appear to be safe. Guidelines from the ESH/ESC

suggest that women at high risk of preeclampsia (from

hypertension in a previous pregnancy, chronic kidney dis-

ease, autoimmune disease, such as systemic lupus erythe-

matosus, or antiphospholipid syndrome, type 1 or 2 diabetes

mellitus, or chronic hypertension), or with more than one

moderate risk factor for preeclampsia (first pregnancy,

age [40 years, pregnancy interval of [10 years, BMI

[35 kg/m2 at first visit, family history of preeclampsia, and

290 C. M. Brown, V. D. Garovic

multiple gestations, e.g. twins), may be advised to take

75 mg of aspirin daily from 12 weeks until the birth of the

baby, provided that they are at low risk of gastrointestinal

hemorrhage [42]. Similarly, the UK NICE guidelines

advise women to take aspirin 75 mg/day from 12 weeks

until birth, if they have at least two moderate risk factors

(as listed above), or if at least one high-risk factor (as

listed above) for preeclampsia exists [43]. They state that

this is an unlicensed indication and that informed consent

should be obtained. There is support for the use of low-

dose aspirin before 16 weeks, with investigators suggest-

ing the possibility that because the transformation of

uterine spiral arteries by trophoblasts is normally com-

pleted by 16–20 weeks, and this is abnormal in pre-

eclampsia, early use of aspirin may be beneficial [44, 45].

6.3 Antioxidants for Preventing Preeclampsia

It has been demonstrated that supplementation with vitamin C

(at a dose of 1,000 mg daily) and vitamin E (at a dose of

400 IU daily) does not reduce the rates of either serious

adverse outcomes of pregnancy-associated hypertension or

preeclampsia among low-risk, nulliparous women [46].

6.4 Calcium Supplementation for Preventing

Hypertensive Disorders

A review of calcium supplementation during pregnancy for

preventing hypertensive disorders concluded that calcium

supplementation appears to approximately halve the risk of

preeclampsia, reduce the risk of preterm birth, and the rare

occurrence of the composite outcome ‘death or serious mor-

bidity’ [47]. Of note, most of the women in these trials had a

low calcium diet and were supplemented with at least 1 g of

calcium daily. However, the evidence for added calcium for

the prevention of hypertensive disorders is conflicting [48].

6.5 Other Agents

Fish oil supplementation and vitamin and nutrient supple-

ments appear to have no benefit in the prevention of

hypertensive disorders [49]. Other management options,

such as the use of corticosteroids, plasma volume expan-

sion, or interventions, such as rest or exercise, have not

been validated [50]. Steroid therapy is recommended only

for lung maturation [30, 31, 43].

Currently, several interventional trials for hypertension

in pregnancy are in progress, including the Control of

Hypertension in Pregnancy Study trial [51], with further

information on these trials being available at ClinicalTri-

als.gov and the WHO International Clinical Trials Registry

Platform. Results from these trials may further enhance our

treatment therapies for hypertension in pregnancy.

7 Novel Therapeutic Targets and Emerging

Treatments

7.1 Angiogenesis

Dysregulation of angiogenesis appears to play a key role in

the pathogenesis of preeclampsia. Placental cystathionine

Table 4 Drug therapy for the treatment of very high blood pressure in pregnancy

Reference Study design Study group Drugs compared Side effectsa

Duley

et al.

[67]

Review of drugs used in

pregnancy for tx of very high

BP, DBP C105 mmHg and/

or SBP 160 mmHg

35 trials

identified,

3,573

women

Labetalol vs. hydralazine; labetalol vs. CCBs;

labetalol vs. methyldopa; labetalol vs.

diazoxide; hydralazine vs. CCBs; hydralazine

vs. diazoxide; hydralazine vs. prostacyclin;

hydralazine vs. ketanserin; hydralazine vs.

urapidil; methyldopa vs. atenolol; nifedipine

vs. prazosin; nifedipine vs. chlorpromazine;

nitrates vs. MgSO4; nimodipine vs. MgSO4;

urapidil vs. CCBs

Hydralazine

headache, flushing, light

headedness, nausea and

palpitations

Labetalol

flushing, light headedness,

palpitations and scalp

tingling

Nifedipine

flushing, nausea, vomiting

Urapidil

nausea and tinnitus

MgSO4

flushing

Methyldopa

somnolence

BP blood pressure, CCBs calcium channel blockers, DBP diastolic BP, MgSO4 magnesium sulphate, SBP systolic BP, tx treatmenta Few trials provided specific side effects

Drug Treatment of Hypertension in Pregnancy 291

c-lyse (CSE) expression is reduced in preeclampsia, lead-

ing to reduced plasma levels of the pro-angiogenic gaseous

vasodilator, hydrogen sulfide (H2S), and increased sFlt-1

[52]. Targeting CSE/H2S activity may be a potential ther-

apy pending additional studies.

7.2 Aminopeptidases

Aminopeptidases, such as placental leucine aminopepti-

dase (P-LAP) and aminopeptidase A (APA), do not cross

the placental barrier. In the pregnant, spontaneously

hypertensive rat, APA acts as an antihypertensive agent,

degrading vasoactive peptides, and as a result, normalizes

BP [53]. The role of aminopeptidases as potential thera-

peutic agents is being investigated.

7.3 Heme Oxygenase 1

A recent study examined heme oxygenase (HO)-1 induc-

tion in a rat model of placental ischemia. George et al. [54]

suggest two potential pathways through which HO-1 acts,

namely, normalization of angiogenic balance in the pla-

centa, and reduction in oxidative stress. Both pathways are

potential targets for treatment in preeclampsia.

7.4 Marinobufagenin

Uddin et al. [55], and others, have investigated the role of

marinobufagenin (MBG), a cardiotonic steroid, and its

antagonist, resibufogenin (RBG), in experimental animal

models of preeclampsia. This group has demonstrated that

in a rat model of preeclampsia, MBG inhibits first tri-

mester cytotrophoblast cell function and that urinary

excretion of MBG is elevated prior to the development of

hypertension and proteinuria. MBG also causes hypoxia

and ischemia, leading to an imbalance of pro- and anti-

angiogenic factors. RBG, when given early in pregnancy,

prevented the development of hypertension, proteinuria,

and IUGR.

7.5 G Protein-Coupled Receptor Targets

There is potential for investigation of novel G Protein-

Coupled Receptor (GPCR)-based therapies in preeclampsia,

including calcitonin receptor-like receptor/receptor activity-

modifying protein 1 complexes, the angiotensin AT1, 2 and

Mas receptors, and the relaxin receptor RXFP1 [56].

7.6 Inhibitors of the Enzyme Poly ADP Ribose

Polymerase

In states of increased oxidative stress, such as diabetes,

overstimulation of poly ADP ribose polymerase (PARP)

leads to endothelial dysfunction, and PARP inhibitors have

been shown to be of benefit [57]. A recent investigation has

demonstrated a protective effect of a PARP inhibitor,

preventing the development of both endothelial dysfunc-

tion and hypertension, in a rat model of preeclampsia [57].

7.7 Gasotransmitters

Nitric oxide, a potent vasodilator that mediates endothe-

lium-dependent relaxation, has been linked to endothelial

dysfunction in preeclampsia [58]. Carbon monoxide (CO),

nitric oxide, and hydrogen sulphide are endogenously

generated gaseous transmitters known as gasotransmitters.

In preclinical animal models, the therapeutic use of CO gas

and CO-releasing molecules demonstrated anti-inflamma-

tory properties and cardiovascular protective effects [59].

These gaseous molecules may have a potential role in the

therapeutics for several diseases, including CVD and pre-

eclampsia, although their instability and potential toxicity

are significant drawbacks.

7.8 Podocytes

Derangements of podocytes and podocyte-specific proteins

are implicated in preeclampsia. There is evidence of an

association between dysregulated pro-angiogenic factors,

hypertension, and podocyte injury. Further investigation

focusing on the mechanism of podocyte injury and

detachment may identify novel therapeutic targets.

These are only a few of the more recent potential ther-

apeutic targets under investigation.

8 Perspectives in Management

Over the last decade, new evidence has emerged, both with

respect to the pathophysiology of preeclampsia and the

benefits of early hypertension treatment in the general

population, which may affect the management of hyper-

tensive pregnant patients. The notion that pregnant women

with chronic hypertension are at low risk for cardiovascular

complications within the short duration of pregnancy may

be in question given the current trend towards advanced

maternal age at first pregnancy. These women may have

other cardiovascular risk factors, such as obesity or

hyperlipidemia, and/or signs of target organ hypertensive

damage. In addition, modern methods of assisted repro-

duction (such as in vitro fertilization) have enabled women

with CVD risk factors that are associated with decreased

fertility (such as diabetes mellitus and renal disease) to

conceive. In these women, treatment of hypertension of

even a short duration may improve their cardiovascular

risks, especially in view of recent studies in the general

292 C. M. Brown, V. D. Garovic

population showing an important correlation between the

time taken to achieve goal BP and clinical outcomes,

namely better outcomes with earlier and more effective

treatment [60, 61]. Finally, recent studies have indicated

that cerebrovascular events in women with severe pre-

eclampsia and eclampsia may occur when the SBP exceeds

150 mmHg, and called for a paradigm shift, by recom-

mending antihypertensive therapy when the SBP reaches or

exceeds 155–160 mmHg [62]. Indeed, most investigators

agree that antihypertensive therapy in the peripartum per-

iod should be initiated when the DBP approaches

100 mmHg, or for a BP C150/100 mmHg [63]. As abrupt

decreases in BP may adversely affect uteroplacental per-

fusion, treatment of hypertension mandates close maternal

and fetal monitoring as the BP is lowered. The ultimate

therapeutic goal is to prevent maternal complications

without compromising fetal wellbeing.

Acknowledgments The project described was supported by award

number P50AG44170 from the National Institute on Aging (Vesna D.

Garovic). Dr. Garovic is the inventor of technology referenced in this

manuscript. That technology has been patented by the Mayo Clinic,

but is currently not licensed. Dr. Brown has no potential conflicts of

interest that might be relevant to the content of this manuscript.

Appendices

Appendix 1: The NHBPEP Working Group Report

on High Blood Pressure in Pregnancy reviewed

and classified studies providing evidence supporting

their recommendations. They used the following

explanatory symbols and appended them to some

of their references and to some of their citations [1]

M: Meta-analysis; an analysis of a compendium of

experimental studies

Ra: Randomized controlled studies

Re: Retrospective analyses; case-control studies

F: Prospective follow-up; cohort studies

X: Cross-sectional population studies

Pr: Previous review or position statements

C: Clinical interventions (nonrandomized)

Appendix 2: ACOG evidence base

I: Evidence obtained from at least one properly ran-

domized controlled trial

II-1: Evidence from well designed controlled trials

without randomization

II-2: Evidence from well designed cohort or case-control

studies, preferably from more than one center or research

group

II-3: Evidence obtained from multiple time series with or

without the intervention. Dramatic results in uncontrolled

experiments could also be regarded as this type of evidence

III: Opinions of respected authorities, based on clinical

experience, descriptive studies, or reports of expert

committees

Recommendations are provided and graded according to

the following categories:

Level A: Recommendations are based on good and

consistent scientific evidence

Level B: Recommendations are based on limited or

inconsistent scientific evidence

Level C: Recommendations are based primarily on

consensus and expert opinion

Appendix 3: Key to evidence statements and grading

of recommendations, using the ranking of the Canadian

Task Force on Preventive Health Care

Quality of Evidence Assessmenta Classification of

Recommendationsb

I: Evidence obtained from at least one properly

randomized controlled trial

II-1: Evidence from well designed controlled trials

without randomization

II-2: Evidence from well designed cohort (prospective or

retrospective) or case-control studies, preferably from

more than one center or research group

II-3: Evidence obtained from comparisons between

times or places with or without the intervention.

Dramatic results in uncontrolled experiments (such as

the results of treatment with penicillin in the 1940s)

could also be included in this category

III: Opinions of respected authorities, based on clinical

experience, descriptive studies, or reports of expert

committees

A. There is good evidence to recommend the clinical

preventive action

B. There is fair evidence to recommend the clinical

preventive action

C. The existing evidence is conflicting and does not

allow the making of a recommendation for or against use

of the clinical preventive action; however, other factors

may influence decision making

D. There is fair evidence to recommend against the

clinical preventive action

E. There is good evidence to recommend against the

clinical preventive action

I. There is insufficient evidence (in quantity or quality)

to make a recommendation; however, other factors may

influence decision making

Drug Treatment of Hypertension in Pregnancy 293

aThe quality of evidence reported in these guidelines has

been adapted from the Evaluation of Evidence criteria

described in the Canadian Task Force on Preventive Health

CarebRecommendations included in these guidelines have

been adapted from the Classification of Recommendations

criteria described in the Canadian Task Force on Pre-

ventive Health Care

Appendix 4: Explanation of the class

of recommendations and levels of evidence used

by the ESH/ESC

Classes of recommendations

Class I: Evidence and/or general agreement that a given

treatment or procedure is beneficial, useful, effective (is

recommended/is indicated)

Class II: Conflicting evidence and/or a divergence of

opinion about the usefulness/efficacy of the given

treatment or procedure

Class IIa: Weight of evidence/opinion is in favor of

usefulness/efficacy (should be considered)

Class IIb: Usefulness/efficacy is less well established by

evidence/opinion (may be considered)

Class III: Evidence or general agreement that the given

treatment or procedure is not useful/effective, and in

some cases may be harmful (is not recommended)

Levels of evidence

Level of evidence A: Data derived from multiple

randomized clinical trials or meta-analyses

Level of evidence B: Data derived from a single random-

ized clinical trial or large non-randomized studies

Level of evidence C: Consensus of opinion of the experts

and/or small studies, retrospective studies, registries

References

1. Report of the National High Blood Pressure Education Program

Working Group on High Blood Pressure in Pregnancy. Am J

Obstet Gynecol. 2000;183(1):S1–22.

2. Homer CS, Brown MA, Mangos G, Davis GK. Non-proteinuric

pre-eclampsia: a novel risk indicator in women with gestational

hypertension. J Hypertens. 2008;26(2):295–302. doi:10.1097/

HJH.0b013e3282f1a953.

3. Pettit F, Brown MA. The management of pre-eclampsia: what we

think we know. Eur J Obstet Gynecol Reprod Biol.

2012;160(1):6–12. doi:10.1016/j.ejogrb.2011.09.049.

4. Trogstad L, Magnus P, Stoltenberg C. Pre-eclampsia: risk factors

and causal models. Best Pract Res Clin Obstet Gynaecol.

2011;25(3):329–42.

5. James JL, Whitley GS, Cartwright JE. Pre-eclampsia: fitting

together the placental, immune and cardiovascular pieces.

J Pathol. 2010;221(4):363–78. doi:10.1002/path.2719.

6. Wang A, Rana S, Karumanchi SA. Preeclampsia: the role of

angiogenic factors in its pathogenesis. Physiology. 2009;24:

147–58. doi:10.1152/physiol.00043.2008.

7. Hertig A, Liere P. New markers in preeclampsia. Clin Chim Acta.

2010;411(21–22):1591–5. doi:10.1016/j.cca.2010.07.020.

8. Steegers EA, von Dadelszen P, Duvekot JJ, Pijnenborg R. Pre-

eclampsia. Lancet. 2010;376(9741):631–44. doi:10.1016/S0140-

6736(10)60279-6.

9. Cetin I, Huppertz B, Burton G, Cuckle H, Gonen R, Lapaire O,

et al. Pregenesys pre-eclampsia markers consensus meeting: what

do we require from markers, risk assessment and model systems

to tailor preventive strategies? Placenta. 2011;32(Suppl):S4–16.

doi:10.1016/j.placenta.2010.11.022.

10. Brown CM, Garovic VD. Mechanisms and management of

hypertension in pregnant women. Curr Hypertens Rep.

2011;13:338–46. doi:10.1007/s11906-011-0214-y.

11. Jonsdottir LS, Arngrimsson R, Geirsson RT, Sigvaldason H,

Sigfusson N. Death rates from ischemic heart disease in women

with a history of hypertension in pregnancy. Acta Obstet Gynecol

Scand. 1995;74(10):772–6.

12. Smith G, Pell J, Walsh D. Pregnancy complications and maternal

risk of ischaemic heart disease: a retrospective cohort study of

129 290 births. Lancet. 2001;357(9273):2002–6. doi:10.1016/

s0140-6736(00)05112-6.

13. Wilson BJ, Watson MS, Prescott GJ, Sunderland S, Campbell

DM, Hannaford P, et al. Hypertensive diseases of pregnancy and

risk of hypertension and stroke in later life: results from cohort

study. BMJ. 2003;326(7394):845. doi:10.1136/bmj.326.7394.

845.

14. ACOG. Practice bulletin #33: diagnosis and management of

preeclampsia and eclampsia. Obstet Gynecol. 2002;99(1):

159–67.

15. ACOG Practice Bulletin. Chronic hypertension in pregnancy.

ACOG Committee on Practice Bulletins. Obstet Gynecol.

2001;98(1 suppl):177–85.

16. Hypertension in pregnancy. Report of the American College of

Obstetricians and Gynecologists’ Task Force on Hypertension in

Pregnancy. Obstet Gynecol. 2013;122(5):1122–31. doi:10.1097/

01.AOG.0000437382.03963.88.

17. Anderson GD, Carr DB. Effect of pregnancy on the pharmaco-

kinetics of antihypertensive drugs. Clin Pharmacokinet. 2009;

48(3):159–68. doi:10.2165/00003088-200948030-00002.

18. Magee LA. Drugs in pregnancy. Antihypertensives. Best Pract

Res Clin Obstet Gynaecol. 2001;15(6):827–45. doi:10.1053/beog.

2001.0232.

19. Podymow T, August P. Update on the use of antihypertensive

drugs in pregnancy. Hypertension. 2008;51(4):960–9. doi:10.

1161/HYPERTENSIONAHA.106.075895.

20. James PR, Nelson-Piercy C. Management of hypertension before,

during, and after pregnancy. Heart. 2004;90(12):1499–504.

doi:10.1136/hrt.2004.035444.

21. Cockburn J, Moar VA, Ounsted M, Redman CW. Final report of

study on hypertension during pregnancy: the effects of specific

treatment on the growth and development of the children. Lancet.

1982;1(8273):647–9.

22. Khalil A, Harrington K, Muttukrishna S, Jauniaux E. Effect of

antihypertensive therapy with alpha-methyldopa on uterine artery

Doppler in pregnancies with hypertensive disorders. Ultrasound

Obstet Gynecol. 2010;35(6):688–94. doi:10.1002/uog.7611.

23. Magee LA. Treating hypertension in women of child-bearing age

and during pregnancy. Drug Saf. 2001;24(6):457–74.

24. Rothberger S, Carr D, Brateng D, Hebert M, Easterling TR.

Pharmacodynamics of clonidine therapy in pregnancy: a hetero-

geneous maternal response impacts fetal growth. Am J Hyper-

tens. 2010;23(11):1234–40. doi:10.1038/ajh.2010.159.

294 C. M. Brown, V. D. Garovic

25. Horvath JS, Phippard A, Korda A, Henderson-Smart DJ, Child A,

Tiller DJ. Clonidine hydrochloride—a safe and effective antihy-

pertensive agent in pregnancy. Obstet Gynecol. 1985;66(5):

634–8.

26. Podymow T, August P. Antihypertensive drugs in pregnancy.

Semin Nephrol. 2011;31(1):70–85. doi:10.1016/j.semnephrol.

2010.10.007.

27. Butters L, Kennedy S, Rubin PC. Atenolol in essential hyper-

tension during pregnancy. BMJ. 1990;301(6752):587–9.

28. Magee LA, Cham C, Waterman EJ, Ohlsson A, von Dadelszen P.

Hydralazine for treatment of severe hypertension in pregnancy:

meta-analysis. BMJ. 2003;327(7421):955–60. doi:10.1136/bmj.

327.7421.955.

29. Abalos E, Duley L, Steyn DW, Henderson-Smart DJ. Antihy-

pertensive drug therapy for mild to moderate hypertension during

pregnancy. Cochrane Database Syst Rev. 2007(1):CD002252.

doi:10.1002/14651858.CD002252.pub2.

30. Lowe SA, Brown MA, Dekker GA, Gatt S, McLintock CK,

McMahon LP, et al. Guidelines for the management of hyper-

tensive disorders of pregnancy 2008. Aust N Z J Obstet Gynae-

col. 2009;49(3):242–6. doi:10.1111/j.1479-828X.2009.01003.x.

31. Magee LA, Helewa M, Moutquin JM, von Dadelszen P. Hyper-

tension Guideline Committee, Society of Obstetricians and

Gynaecologists of Canada. Treatment of the hypertensive disor-

ders of pregnancy. In: Diagnosis, evaluation, and management of

the hypertensive disorders of pregnancy. J Obstet Gynaecol Can.

2008;30(3 Suppl 1):S24–36.

32. Magee LA, Schick B, Donnenfeld AE, Sage SR, Conover B,

Cook L, et al. The safety of calcium channel blockers in human

pregnancy: a prospective, multicenter cohort study. Am J Obstet

Gynecol. 1996;174(3):823–8.

33. Papatsonis DN, Lok CA, Bos JM, Geijn HP, Dekker GA. Cal-

cium channel blockers in the management of preterm labor and

hypertension in pregnancy. Eur J Obstet Gynecol Reprod Biol.

2001;97(2):122–40.

34. Widerlov E, Karlman I, Storsater J. Hydralazine-induced neo-

natal thrombocytopenia. N Engl J Med. 1980;303(21):1235.

35. Shoemaker CT, Meyers M. Sodium nitroprusside for control of

severe hypertensive disease of pregnancy: a case report and

discussion of potential toxicity. Am J Obstet Gynecol.

1984;149(2):171–3.

36. Sibai BM, Grossman RA, Grossman HG. Effects of diuretics on

plasma volume in pregnancies with long-term hypertension. Am J

Obstet Gynecol. 1984;150(7):831–5.

37. Jim B, Sharma S, Kebede T, Acharya A. Hypertension in preg-

nancy: a comprehensive update. Cardiol Rev. 2010;18(4):178–89.

doi:10.1097/CRD.0b013e3181c60ca6.

38. Cooper WO, Hernandez-Diaz S, Arbogast PG, Dudley JA, Dyer

S, Gideon PS, et al. Major congenital malformations after first-

trimester exposure to ACE inhibitors. N Engl J Med.

2006;354(23):2443–51. doi:10.1056/NEJMoa055202.

39. Bateman BT, Hernandez-Diaz S, Huybrechts KF, Palmsten K,

Mogun H, Ecker JL, et al. Patterns of outpatient antihypertensive

medication use during pregnancy in a Medicaid population.

Hypertension. 2012;60(4):913–20. doi:10.1161/

HYPERTENSIONAHA.112.197095.

40. Duley L, Gulmezoglu AM, Henderson-Smart DJ, Chou D.

Magnesium sulphate and other anticonvulsants for women with

pre-eclampsia. Cochrane Database Syst Rev. 2010;11:CD000025.

doi:10.1002/14651858.CD000025.pub2.

41. Duley L, Henderson-Smart DJ, Meher S, King JF. Antiplatelet

agents for preventing pre-eclampsia and its complications.

Cochrane Database Syst Rev. 2007(2):CD004659. doi:10.1002/

14651858.CD004659.pub2.

42. Mancia G, Fagard R, Narkiewicz K, Redon J, Zanchetti A, Bohm

M, et al. 2013 ESH/ESC Guidelines for the management of

arterial hypertension: the Task Force for the management of

arterial hypertension of the European Society of Hypertension

(ESH) and of the European Society of Cardiology (ESC). J Hy-

pertens. 2013;31(7):1281–357. doi:10.1097/01.hjh.0000431740.

32696.cc.

43. Hypertension in pregnancy: the management of hypertensive

disorders during pregnancy. London: NICE 2010. Report No.:

CG107.

44. Bujold E, Roberge S, Lacasse Y, Bureau M, Audibert F, Marcoux

S, et al. Prevention of preeclampsia and intrauterine growth

restriction with aspirin started in early pregnancy: a meta-ana-

lysis. Obstet Gynecol. 2010;116(2 Pt 1):402–14. doi:10.1097/

AOG.0b013e3181e9322a.

45. Bujold E. Prevention of pre-eclampsia with low-dose aspirin.

J Postgrad Med. 2011;57(2):89–90. doi:10.4103/0022-3859.

81857.

46. Roberts JM, Myatt L, Spong CY, Thom EA, Hauth JC, Leveno

KJ, et al. Vitamins C and E to prevent complications of preg-

nancy-associated hypertension. N Engl J Med. 2010;362(14):

1282–91. doi:10.1056/NEJMoa0908056.

47. Hofmeyr GJ, Lawrie TA, Atallah AN, Duley L. Calcium sup-

plementation during pregnancy for preventing hypertensive dis-

orders and related problems. Cochrane Database Syst Rev.

2010(8):CD001059. doi:10.1002/14651858.CD001059.pub3.

48. European Society of Gynecology, Association for European

Paediatric C, German Society for Gender Medicine, Regitz-

Zagrosek V, Blomstrom Lundqvist C, Borghi C, et al. ESC

Guidelines on the management of cardiovascular diseases during

pregnancy: the Task Force on the Management of Cardiovascular

Diseases during Pregnancy of the European Society of Cardiol-

ogy (ESC). Eur Heart J. 2011;32(24):3147–97. doi:10.1093/

eurheartj/ehr218.

49. Olsen SF, Osterdal ML, Salvig JD, Weber T, Tabor A, Secher

NJ. Duration of pregnancy in relation to fish oil supplemen-

tation and habitual fish intake: a randomised clinical trial with

fish oil. Eur J Clin Nutr. 2007;61(8):976–85. doi:10.1038/sj.

ejcn.1602609.

50. Duley L. The global impact of pre-eclampsia and eclampsia.

Semin Perinatol. 2009;33(3):130–7. doi:10.1053/j.semperi.2009.

02.010.

51. Magee LA, von Dadelszen P, Chan S, Gafni A, Gruslin A, He-

lewa M et al. the control of hypertension in pregnancy study pilot

trial. BJOG. 2007;114(6):770, e13–20. doi:10.1111/j.1471-0528.

2007.01315.x.

52. Wang K, Ahmad S, Cai M, Rennie J, Fujisawa T, Crispi F,

et al. Dysregulation of hydrogen sulfide producing enzyme

cystathionine gamma-lyase contributes to maternal hyperten-

sion and placental abnormalities in preeclampsia. Circulation.

2013;127(25):2514–22. doi:10.1161/CIRCULATIONAHA.

113.001631.

53. Mizutani S, Wright JW, Kobayashi H. Placental leucine amino-

peptidase- and aminopeptidase A-deficient mice offer insight

concerning the mechanisms underlying preterm labor and pre-

eclampsia. J Biomed Biotechnol. 2011;2011:286947. doi:10.

1155/2011/286947.

54. George EM, Cockrell K, Aranay M, Csongradi E, Stec DE,

Granger JP. Induction of heme oxygenase 1 attenuates placental

ischemia-induced hypertension. Hypertension. 2011;57:941–8.

doi:10.1161/hypertensionaha.111.169755.

55. Uddin MN, Horvat D, DeMorrow S, Agunanne E, Puschett JB.

Marinobufagenin is an upstream modulator of Gadd45a stress

signaling in preeclampsia. Biochim Biophys Acta. 2011;1812(1):

49–58. doi:10.1016/j.bbadis.2010.09.006.

56. McGuane J, Conrad K. GPCRs as potential therapeutic targets in

preeclampsia. Drug Discov Today Dis Models. 2012;9(3):

e119–27. doi:10.1016/j.ddmod.2012.05.001.

Drug Treatment of Hypertension in Pregnancy 295

57. Walsh SK, English FA, Crocker IP, Johns EJ, Kenny LC. Con-

tribution of PARP to endothelial dysfunction and hypertension in

a rat model of pre-eclampsia. Br J Pharmacol. 2012;166(7):

2109–16. doi:10.1111/j.1476-5381.2012.01906.x.

58. Lowe DT. Nitric oxide dysfunction in the pathophysiology of

preeclampsia. Nitric Oxide. 2000;4(4):441–58. doi:10.1006/niox.

2000.0296.

59. Motterlini R, Otterbein LE. The therapeutic potential of carbon

monoxide. Nat Rev Drug Discov. 2010;9(9):728–43. doi:10.

1038/nrd3228.

60. Weber MA, Julius S, Kjeldsen SE, Brunner HR, Ekman S,

Hansson L, et al. Blood pressure dependent and independent

effects of antihypertensive treatment on clinical events in the

VALUE Trial. Lancet. 2004;363(9426):2049–51. doi:10.1016/

S0140-6736(04)16456-8.

61. Gradman AH, Basile JN, Carter BL, Bakris GL. Combination

therapy in hypertension. J Am Soc Hypertens. 2010;4(1):42–50.

doi:10.1016/j.jash.2010.02.005.

62. Martin JN Jr, Thigpen BD, Moore RC, Rose CH, Cushman J,

May W. Stroke and severe preeclampsia and eclampsia: a para-

digm shift focusing on systolic blood pressure. Obstet Gynecol.

2005;105(2):246–54. doi:10.1097/01.AOG.0000151116.84113.

56.

63. August P. Preeclampsia: new thoughts on an ancient problem.

J Clin Hypertens. 2000;2(2):115–23.

64. Antenatal Care. Routine care for the healthy pregnant woman.

London: National Institute for Health and Clinical Excellence:

Guidance; 2008.

65. O’Brien E, Parati G, Stergiou G, Asmar R, Beilin L, Bilo G, et al.

European society of hypertension position paper on ambulatory

blood pressure monitoring. J Hypertens. 2013;31(9):1731–68.

doi:10.1097/HJH.0b013e328363e964.

66. Mancia G, De Backer G, Dominiczak A, Cifkova R, Fagard R,

Germano G, et al. 2007 Guidelines for the Management of

Arterial Hypertension: the Task Force for the Management of

Arterial Hypertension of the European Society of Hypertension

(ESH) and of the European Society of Cardiology (ESC). J Hy-

pertens. 2007;25(6):1105–87. doi:10.1097/HJH.0b013e32

81fc975a.

67. Duley L, Meher S, Jones L. Drugs for treatment of very high

blood pressure during pregnancy. Cochrane Database Syst Rev.

2013;7:CD001449. doi:10.1002/14651858.CD001449.pub3.

68. Moser M, Brown CM, Rose CH, Garovic VD. Hypertension in

pregnancy: is it time for a new approach to treatment? J Hyper-

tens. 2012;30(6):1092–100. doi:10.1097/HJH.0b013e328

3536319

296 C. M. Brown, V. D. Garovic

Copyright of Drugs is the property of Springer Science & Business Media B.V. and itscontent may not be copied or emailed to multiple sites or posted to a listserv without thecopyright holder's express written permission. However, users may print, download, or emailarticles for individual use.